This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. These studies focus on states of negative energy balance that are associated with a suppression of reproductive function. The identity of the specific metabolic signals or afferent neural pathways that convey information about energy balance to gonadotropin-releasing hormone (GnRH) neurons, the central hypothalamic system regulating reproduction, remains elusive. A key hypothesis of this project is that suppression of kisspeptin signaling is the primary factor in the inhibition of GnRH. Although it is a widely held view that hypoleptinemia is the critical factor linking energy balance and suppressed GnRH, our recent studies demonstrate that restoring leptin to normal physiological levels does not reverse the inhibition of kisspeptin or GnRH in either lactation or caloric restriction. Thus, hypoleptinemia does not appear to be the primary metabolic factor responsible for the suppression of reproductive function. Our hypothesis is that brainstem systems, such as glucose sensing neurons, may be the site where information about metabolic signals is relayed to kisspeptin neurons. This project focuses on two hypotheses: 1) Suppression of kisspeptin signaling at the site of GnRH cell bodies and at nerve fibers and terminals are primary components in its inhibition during states of negative energy balance, and 2) Brainstem systems serve as a site of integration of metabolic signals and provide the afferent signals that are responsible for the suppression of kisspeptin during negative energy balance. These studies will identify new pathways that regulate control GnRH neurons and could lead to new treatments for restoring fertility in states of negative energy balance.